TDM du Sorafenib -...

TDM du Sorafenib

Dr Benoit BLANCHETUF de Pharmacocinétique et Pharmacochimie

Hôpital Cochin1

Sorafenib

Rini B, Br J Cancer 2007

Tous grades (%) Grades 3-4 (%)

SMP 47 12

HTA 14 4

Diarrhée 43 5

Fatigue 34 8

Principales toxicités (Etude EU-ARCCS)

Indications : • Hépatocarcinome• Carcinome rénal métastatique• Cancer de la thyroïde réfractaire à l’iode

Beck et al., Annal Oncol 2011

Pharmacocinétique

3

Biodisponibilitéa (%) 38-49

Influence nourriture ➘ 29% AUC si repas riche en lipides

Fixation protéique (%) ~ 99

Métabolisme CYP3A4/UGT1A9

Métabolite actif M2 (17% dans plasma vs 73% sorafenib)

Cycle entérohépatique Oui

Elimination Biliaire

Demi-vie (heures) 20-39

Substrat protéines d’efflux Pg-P, BCRP

Pharmacocinétique linéaire oui —> 400 mg x 2/j

aBiodisponibilité relative

Overview sorafenib

Variabilité pharmacocinétique

4De wit et al., Drug Discovery, 2015

studies have shown exposure–efficacy and exposure–toxicity rela-

tions. Rash is often suggested as a potential early biomarker to

select patients in need for dose adjustment, although dosing to

rash did not improve clinical activity. Furthermore, in studies that

showed correlations between PK and treatment outcome and/or

toxicity and treatment outcome, PK parameters were not always

related to toxicity. In our opinion, it is unlikely that rash can be

used to individualize erlotinib therapy because dosing to rash did

not demonstrate improved treatment outcomes.

GefitinibCorrelation between exposure and efficacySimilar to erlotinib, a study in 44 patients with NSCLC measured

trough levels [74]. A high Ctrough day 8:Ctrough day 3 ratio was

associated with better PFS (P = 0.0158), although individual

trough levels were not related to longer PFS. Furthermore, no

correlation with OS was found. A prospective study in 30 patients

with NSCLC showed that patients with high gefitinib exposure

(Ctrough ! 200 ng/ml) had longer OS (P = 0.007) compared with

patients with low exposure (Ctrough < 200 ng/ml) [75]. Addition-

ally, the patients with wild type epidermal growth factor receptor

(EGFR) appeared to be more sensitive to higher exposure levels

with longer survival ("2 months longer median OS) compared

with the other patients. Finally, in a dose escalation to skin toxicity

study with 20 patients with HNSCC, trough levels for patients with

disease control (PR + SD) were higher compared with patients with

PD (1117 versus 520 ng/ml, P = 0.0103) [76].

Correlation between exposure and toxicityDifferent phase I studies explored a possible relation between

gefitinib plasma concentrations and skin- and gastrointestinal

toxicity [77–79]. Zhao et al. showed that patients with high gefi-

tinib exposure (Ctrough ! 200 ng/ml) experienced more rash

(P = 0.043) compared with patients with low exposure

(Ctrough < 200 ng/ml) [75]. The incidence of gastrointestinal tox-

icity was not found to differ between the two groups [75]. Howev-

er, in the population PK analysis of Li et al., gefitinib Ctrough level

was a significant predictor for the incidence of !grade 1 diarrhea

(P < 0.05) [80].

Inter- and intrapatient variability in exposureGefitinib shows large interpatient variability in AUC (31–112%),

Cl/F (79–90%) and Ctrough (14–166%) [75,77,78,81–98]. The intra-

patient variability for Ctrough is 2–49% [77,91]. A phase I study

designed to determine the intrapatient variability, showed a two-

fold variability in AUC within subjects, whereas the variability

between patients was 15-fold [85]. Population PK studies indicated

that gender, age, bodyweight, ethnicity, or creatinine clearance

cannot explain the large interpatient variability [99].

Dose individualizationThere are three dose individualization studies published for gefi-

tinib; two phenotyping studies and one toxicity-driven dosing

study [76,80,100]. Given that Cytochrome P450, family 3, sub-

family A (CYP3A) is the principal enzyme that metabolizes gefi-

tinib, variability in its activity might be an explanation of PK

variability. The first phenotyping study showed that midazolam

oral clearance as a measure of CYP3A activity accounted for 37% of

the interpatient variability in gefitinib oral clearance [80]. Further-

more, midazolam clearance was strongly associated with both

gefitinib clearance (R2 = 0.68) and gefitinib Ctrough (R2 = 0.58).

Therefore, midazolam could be used to identify those patients

at risk for under- or overdosing, respectively. The second pheno-

typing study showed a borderline significant correlation between

midazolam and gefitinib AUC [100].

In a dose escalation study in patients with HNSCC, the gefitinib

dose was escalated from 500 to 750 mg in those patients without

grade 2 skin toxicity [76]. In the preplanned analysis of patients

with and without !grade 2 skin toxicity, there was no difference

observed in treatment benefit.

ConclusionThe intrapatient variability in gefitinib PK appears small compared

with the large interpatient variability. Further investigation to

REVIEWS Drug Discovery Today # Volume 20, Number 1 # January 2015

TABLE 5

PK inter- and intrapatient variability of TKIsa

TKI Interpatient variability (CV%) Intrapatient variability (CV%) Refs

Ctrough AUCb CL/F (l/hour) Ctrough AUCb CL/F (l/hour)

Axitinib N/A 17–94% 17–113% 20–22% 20–33% 20–22% [21,22,24–26]

Dabrafenib 119% 38–68% 59% N/A N/A N/A [29,30]

Erlotinib 38–76% 18–156% 10–129% N/A 16–24% N/A [40,42,47,51–72]

Gefitinib 14–166% 31–112% 79–90% 2–49% 14% N/A [75,77,78,81–98]

Imatinib 25–64% 21–66% 17–88% 15–27% 12% N/A [4,105–123]

Lapatinib 55–97% 42–117% 48% N/A 30–36% N/A [147–159,145,160–162]

Pazopanib 11–90% 19–77% N/A N/A N/A N/A [158,163,165,167,168,170,171]

Regorafenib 57% 43-88% N/A N/A 34% N/A [172,174–176]

Sorafenib 25–104% 12–117% 13–80% N/A 31–47% N/A [92,177–180,184–210]

Sunitinib 34–59% 13–49% 28–46% N/A N/A N/A [209,216,220–236]

Vandetanib 20–56% 8–99% 8–55% N/A 8% N/A [245–253]

Vemurafenib N/A 28–52% 32–54% N/A N/A N/A [255–258]a Abbreviations: %CV, coefficient of variation; CL/F, apparent oral clearance; Ctrough, minimum plasma concentration level; N/A, not available.b AUC1 following a single dose or AUC over the dosing interval at steady state.

26 www.drugdiscoverytoday.com

Reviews#FO

UNDATION

REV

IEW

48,2†20094135,6400 x 4

10,9**150,170,5101,7400 x 3

139,562,191,5800 x 2

150,170,5101,7400 x 3

24,6

12255,981,6600 x 2

102,550,471,3200 x 3

5,2

100,047,067,8400 x 2

Augmentation AUC (%)75th25thAUCDose (mg/j)

48,2†20094135,6400 x 4

10,9**150,170,5101,7400 x 3

139,562,191,5800 x 2

150,170,5101,7400 x 3

24,6

12255,981,6600 x 2

102,550,471,3200 x 3

5,2

100,047,067,8400 x 2

Augmentation AUC (%)75th25thDose (mg/j)

Facteur de variabilité : absorption intestinale

5Hornecker et al., Invest New Drugs 2012

0,7

0,6

0,5

0,4

0,3

0,2

0,1

0400(n=88)

Sorafenib daily dose (mg)

>1600(n=24)

800(n=187)

1600(n=38)

1200(n=35)

Ab

solu

teb

ioav

aila

bil

ity

0,7

0,6

0,5

0,4

0,3

0,2

0,1

0400(n=88)


>1600(n=24)

800(n=187)

1600(n=38)

1200(n=35)

Ab

solu

teb

ioav

aila

bil

ity

250

200

150

100

50

0400(n=88)

800(n=187)


So

rafe

nib

AU

C (

mg

/L.h

)

1200(n=35)

1600(n=38)

>1600(n=24)

C250

200

150

100

50

0400(n=88)

800(n=187)


So

rafe

nib

AU

C (

mg

/L.h

)

1200(n=35)

1600(n=38)

>1600(n=24)

C

Chez non-répondeurs

! 3 prises par jour pour dose > 800 mg/j

Facteur de variabilité : polymorphismes génétiques

6Peer et al., Clin Cancer Research 2012

the UGT1A9!3 single-nucleotide polymorphism (SNP)seemed to be the major predictive alleles associated withphenotype.To further study the apparently different phenotypes

for patients carrying only UGT1A1!28 alleles (n ¼ 8),we genotyped 1,936 polymorphisms in 225 genesinvolved in clinical pharmacology with the Drug Metab-olizing Enzymes and Transporters (DMET) Plus panel(Coriell Institute). DMET genotyping was only successful(#90% call rate) in a total of 6 patients with the followingAUCs (ng$h/mL/mg): 2.7, 6.3, 18.0, 109.9, 116.2, 139.6.DMET analysis revealed that only the ABCC2 -24C>T SNPcosegregated with sorafenib metabolism phenotype. Aftersequencing the ABCC2 -24C>T SNP in all patients carry-ing UGT1A1!28/!28, it was determined that the patientwith the lowest observed AUC (i.e., 2.7 ng$h/mL/mg) wasdouble variant, whereas patients with the next lowestAUCs (6.3, 18.0, and 72.5 ng$h/mL/mg) were heterozy-gous followed by those with the highest AUCs (109.9,116.2, and 139.6) who carried homozygous wild-typealleles. A single patient with AUC ¼ 198.6 ng$h/mL/mgwas not ascertainable as ABCC2 genotyping by directsequencing was not successful. Upon sequencing thewhole population for ABCC2 -24C>T, it was determined

that individuals carrying only variant alleles in thisSNP tended to have lower median AUC (29.8 versus40.5 ng$h/mL/mg) than individuals carrying 1 or 2 copiesof wild-type allele, but this was not statistically significant(P ¼ 0.21). Therefore, the ABCC2 -24C>T SNP onlyseems to modify AUC phenotype in those carrying onlyUGT1A1!28 alleles.

Genotype versus bilirubin change following sorafenibBecause previous case-report data indicated that sorafe-

nib might induce bilirubin changes in patients based onUGT1A1 allele status (14, 15), we hypothesized that sor-afenib exposure would correspond to greater increases inpostsorafenibbilirubin concentration in those patientswithlow functioning UGT1A1 alleles (i.e., UGT1A1!28). Analy-sis of bilirubin versus genotype was only conducted in menwith prostate cancer receiving sorafenib as comprehensivebilirubin data were not obtained in other trials. Themedianchange in bilirubin plasma concentration was 0 mg/dL(range ¼ %0.3 to 0.5 mg/dL; n ¼ 45). A total of 3 patientswith normal CrCL developed hyperbilirubinemia (i.e., bil-irubin concentration #1.0 mg/dL) following sorafenib(UGT1A1 (TA)5/(TA)6 n ¼ 1, (TA)6/(TA)7 n ¼ 2), and 2patients that presented with hyperbilirubinemia before thesorafenib dose had a further rise in bilirubin concentrationfollowing sorafenib (UGT1A1 (TA)6/(TA)7 n ¼ 1, (TA)7/(TA)7 n ¼ 1; the latter patient had a 0.4 mg/dL increase).

UGT1A1 A(TA)nTAA status was not related to change inbilirubin from baseline (P ¼ 0.39; Fig. 2A). However,regression analysis indicated that sorafenib exposure wasrelated to bilirubin serum concentration in patients withnormal CrCl (R2 ¼ 0.29; P ¼ 0.0005; Fig. 2B). Whenregression analyses were stratified on the basis of UGT1A1A(TA)nTAA genotype status, this analysis revealed thatsorafenib exposure was not related to bilirubin increasesin patients carrying either UGT1A1 (TA)5/5 or (TA)5/6, orUGT1A1 (TA)6/6 genotypes (R2 ¼ 0.43 and 0.030 respec-tively; P ¼ 0.35 and 0.51, respectively; Fig. 2C and D).However, only 4 individuals carried a copy of UGT1A1(TA)5, and there is an apparent (albeit nonsignificant)proportional increase in both AUC and sorafenib-inducedbilirubin changes consistent with the rather high R2 for thisgenotype grouping. When the data were stratified byUGT1A1 (TA)6/7 and UGT1A1 (TA)7/7 genotypes, a signif-icant (or marginally nonsignificant) relationship wasobserved in both cases with a relatively high correlation(R2 ¼ 0.38 and 0.77 respectively; P ¼ 0.032 0.051,respectively; Fig. 2E and F). For patients with the UGT1A1(TA)6/7 genotype, the data indicate that bilirubin increasedby 0.1 mg/dL for every 25.7 (ng/mL$h/mg) unit increase insorafenib AUC. Carriers of UGT1A1 (TA)7/7 had a similarrelationship between bilirubin and AUC (i.e., a 30.9 ng/mL$h/mgunit increase in AUCcorresponded to a 0.1mg/dLincrease in bilirubin). These data are consistent with pre-vious case reports in which UGT1A1 (TA)6/7 carriers devel-oped jaundice following sorafenib treatment and are alsoconsistent with our results that sorafenib is a mixed inhib-itor of UGT1A1.

Figure 1. Dose-normalized sorafenib AUC versusUGT1A genotype. EachUGT1A9!1/!3 carrier also carried UGT1A1 (TA)6/(TA)7 (AUC ¼ 17.3 and20.2 ng/mL$h/mg) while the single UGT1A9!3/!3 carrier also carriedUGT1A1 (TA)6/(TA)6 (AUC ¼ 153.3 ng/mL$h/mg, as indicated by !).UGT1A-impaired implies patients with deficient UGT1A1 or UGT1A9metabolism based on genetics. Excluded patients (n¼ 38) are describedin the Supplementary Results section and n ¼ 82 individuals wereincluded in this analysis. Of these, AUC data for n ¼ 8 patientsparticipating on BAY-KS were not available; thus potential drug–druginteractions between ritonavir and sorafenib were not accounted for.There was no association between UGT1A1 and UGT1A9 genotypestatus when compared with sorafenib AUC (P ¼ 0.20; Kruskal–WallisANOVA).

UGT1A Variants Affect Sorafenib Pharmacokinetics

www.aacrjournals.org Clin Cancer Res; 18(7) April 1, 2012 2103

on May 16, 2016. © 2012 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst February 3, 2012; DOI: 10.1158/1078-0432.CCR-11-2484

the UGT1A9!3 single-nucleotide polymorphism (SNP)seemed to be the major predictive alleles associated withphenotype.To further study the apparently different phenotypes

for patients carrying only UGT1A1!28 alleles (n ¼ 8),we genotyped 1,936 polymorphisms in 225 genesinvolved in clinical pharmacology with the Drug Metab-olizing Enzymes and Transporters (DMET) Plus panel(Coriell Institute). DMET genotyping was only successful(#90% call rate) in a total of 6 patients with the followingAUCs (ng$h/mL/mg): 2.7, 6.3, 18.0, 109.9, 116.2, 139.6.DMET analysis revealed that only the ABCC2 -24C>T SNPcosegregated with sorafenib metabolism phenotype. Aftersequencing the ABCC2 -24C>T SNP in all patients carry-ing UGT1A1!28/!28, it was determined that the patientwith the lowest observed AUC (i.e., 2.7 ng$h/mL/mg) wasdouble variant, whereas patients with the next lowestAUCs (6.3, 18.0, and 72.5 ng$h/mL/mg) were heterozy-gous followed by those with the highest AUCs (109.9,116.2, and 139.6) who carried homozygous wild-typealleles. A single patient with AUC ¼ 198.6 ng$h/mL/mgwas not ascertainable as ABCC2 genotyping by directsequencing was not successful. Upon sequencing thewhole population for ABCC2 -24C>T, it was determined

that individuals carrying only variant alleles in thisSNP tended to have lower median AUC (29.8 versus40.5 ng$h/mL/mg) than individuals carrying 1 or 2 copiesof wild-type allele, but this was not statistically significant(P ¼ 0.21). Therefore, the ABCC2 -24C>T SNP onlyseems to modify AUC phenotype in those carrying onlyUGT1A1!28 alleles.

Genotype versus bilirubin change following sorafenibBecause previous case-report data indicated that sorafe-

nib might induce bilirubin changes in patients based onUGT1A1 allele status (14, 15), we hypothesized that sor-afenib exposure would correspond to greater increases inpostsorafenibbilirubin concentration in those patientswithlow functioning UGT1A1 alleles (i.e., UGT1A1!28). Analy-sis of bilirubin versus genotype was only conducted in menwith prostate cancer receiving sorafenib as comprehensivebilirubin data were not obtained in other trials. Themedianchange in bilirubin plasma concentration was 0 mg/dL(range ¼ %0.3 to 0.5 mg/dL; n ¼ 45). A total of 3 patientswith normal CrCL developed hyperbilirubinemia (i.e., bil-irubin concentration #1.0 mg/dL) following sorafenib(UGT1A1 (TA)5/(TA)6 n ¼ 1, (TA)6/(TA)7 n ¼ 2), and 2patients that presented with hyperbilirubinemia before thesorafenib dose had a further rise in bilirubin concentrationfollowing sorafenib (UGT1A1 (TA)6/(TA)7 n ¼ 1, (TA)7/(TA)7 n ¼ 1; the latter patient had a 0.4 mg/dL increase).

UGT1A1 A(TA)nTAA status was not related to change inbilirubin from baseline (P ¼ 0.39; Fig. 2A). However,regression analysis indicated that sorafenib exposure wasrelated to bilirubin serum concentration in patients withnormal CrCl (R2 ¼ 0.29; P ¼ 0.0005; Fig. 2B). Whenregression analyses were stratified on the basis of UGT1A1A(TA)nTAA genotype status, this analysis revealed thatsorafenib exposure was not related to bilirubin increasesin patients carrying either UGT1A1 (TA)5/5 or (TA)5/6, orUGT1A1 (TA)6/6 genotypes (R2 ¼ 0.43 and 0.030 respec-tively; P ¼ 0.35 and 0.51, respectively; Fig. 2C and D).However, only 4 individuals carried a copy of UGT1A1(TA)5, and there is an apparent (albeit nonsignificant)proportional increase in both AUC and sorafenib-inducedbilirubin changes consistent with the rather high R2 for thisgenotype grouping. When the data were stratified byUGT1A1 (TA)6/7 and UGT1A1 (TA)7/7 genotypes, a signif-icant (or marginally nonsignificant) relationship wasobserved in both cases with a relatively high correlation(R2 ¼ 0.38 and 0.77 respectively; P ¼ 0.032 0.051,respectively; Fig. 2E and F). For patients with the UGT1A1(TA)6/7 genotype, the data indicate that bilirubin increasedby 0.1 mg/dL for every 25.7 (ng/mL$h/mg) unit increase insorafenib AUC. Carriers of UGT1A1 (TA)7/7 had a similarrelationship between bilirubin and AUC (i.e., a 30.9 ng/mL$h/mgunit increase in AUCcorresponded to a 0.1mg/dLincrease in bilirubin). These data are consistent with pre-vious case reports in which UGT1A1 (TA)6/7 carriers devel-oped jaundice following sorafenib treatment and are alsoconsistent with our results that sorafenib is a mixed inhib-itor of UGT1A1.

Figure 1. Dose-normalized sorafenib AUC versusUGT1A genotype. EachUGT1A9!1/!3 carrier also carried UGT1A1 (TA)6/(TA)7 (AUC ¼ 17.3 and20.2 ng/mL$h/mg) while the single UGT1A9!3/!3 carrier also carriedUGT1A1 (TA)6/(TA)6 (AUC ¼ 153.3 ng/mL$h/mg, as indicated by !).UGT1A-impaired implies patients with deficient UGT1A1 or UGT1A9metabolism based on genetics. Excluded patients (n¼ 38) are describedin the Supplementary Results section and n ¼ 82 individuals wereincluded in this analysis. Of these, AUC data for n ¼ 8 patientsparticipating on BAY-KS were not available; thus potential drug–druginteractions between ritonavir and sorafenib were not accounted for.There was no association between UGT1A1 and UGT1A9 genotypestatus when compared with sorafenib AUC (P ¼ 0.20; Kruskal–WallisANOVA).

UGT1A Variants Affect Sorafenib Pharmacokinetics

www.aacrjournals.org Clin Cancer Res; 18(7) April 1, 2012 2103

on May 16, 2016. © 2012 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst February 3, 2012; DOI: 10.1158/1078-0432.CCR-11-2484

Facteur de variabilité : sarcopénie

7

All Dose Limiting Toxicities (DLT)

Sarcopenic Non-sarcopenic0

20

40

60

80p<0.0006

Inci

denc

e of

DLT

(%

)

Diarrhea (grade 3/4)


20

40

60

80

Inci

denc

e of

DLT

(%

)

p<0.05

Hand Foot Syndrom (grade 3/4)


20

40

60

80

ns

Inci

denc

e of

DLT

(%)

Toxicity present Toxicity absent0

20

40

60

80

Dose Limiting ToxicityLe

an B

ody

Mas

s (k

g)

Mir et al., Plos one, 2012

AUC à J28: 102,4 (sarcopéniques) vs. 53,7 mg/L.h (p = 0,01)

Facteur de variabilité : albuminémie

8Tod et al., Pharm res 2012

Albuminémie : facteur de variabilité de la clairance —> Si hypoalbuminémie, augmentation clairance

Facteur de variabilité : interactions médicamenteuses

9

Gomo et al., Invest New Drugs 2011Lathia et al., Cancer Chemotherapy Pharmacol 2006

• Interaction médicamenteuse : imprévisible • Inhibiteur/substrat CYP3A4 et inducteur

Noda et al., Cancer Chemotherapy Pharmacol 2013

0

20

40

60

80

100

120

140

160

0 10 20 30 40 50 60 70 80

Time after sorafenib initiation (days)

Sor

afen

ib A

UC

(mg/

L.h) Felodipine introduction

(10 mg/day)

Grade 2 diarrhea

Grade 3 anorexia

+SD

- SD

mean

0

20

40

60

80

100

120

140

160

0 10 20 30 40 50 60 70 80

Time after sorafenib initiation (days)

Sor

afen

ib A

UC

(mg/

L.h) Felodipine introduction

(10 mg/day)

Grade 2 diarrhea

Grade 3 anorexia

+SD

- SD

mean

Relation PK/PD : toxicités précoces

10

risk of sorafenib-induced grade $2 diarrhea strongly increaseswhen the T allele in UGT1A9 22152 C.T is present (OR 14.33).This result is particularly interesting because severe diarrhea couldresult in a significant decrease in the bioavailability of sorafenib,which might lead to a decreased systemic drug exposure andpossibly to a lesser anti-tumor efficacy. From a pathophysiologicalpoint of view, sorafenib-induced diarrhea may be related to theglucuronidation of the carboxylic acid M6, which is the majorsorafenib metabolite found in feces (19.1% of the dose) [6]. Thus,the increase in intestinal expression of UGT1A9, and hence inglucuronidation activity related to the UGT1A9 22152 C.Tpolymorphism, may cause a significant biostranformation of thecarboxylic acid M6 to reactive acyl glucuronide metabolites, whichare known to damage enterocytes and cause diarrhea [39]. Thishypothesis could explain the fact that this polymorphism isassociated with severe diarrhea without any impact on sorafenib

systemic exposure. However, due to the small sample size and therelatively low frequency of UGT1A9 variants, further studies arerequired to confirm the association between the UGT1A9 2152C.T polymorphism and diarrhea.

Hand-foot skin reaction was the most prevalent toxicity in thepresent study, which is in consistence with the shorter delay ofoccurrence of this toxicity compared to diarrhea and hypertension.In the present cohort, the risk for developing grade $2 HFSR inthe first month of sorafenib therapy was approximately 5-foldgreater in females compared to males (OR 5.26). This result is inagreement with a recent study which documented female genderas an independent risk factor for developing grade $2 HFSR [32].Finally, the present study highlights for the first time that greatersorafenib exposure in females compared to males over the firstmonth of therapy may be a determining factor of sorafenib-induced HFSR in females.

Table 5. Risk factors associated with sorafenib-induced toxicity, defined as any toxicity $grade 3 or hand foot skin reaction,hypertension and diarrhea grade $2.

Univariate analysis Multivariate analysis

Variable No Yes p-value OR (95% CI) p-value

Any toxicity $ grade 3

Gender 0.024 NS

Female, n (%) 5 (33.3) 10 (66.7)

Male, n (%) 25 (67.6) 12 (32.4)

CYP3A5 6986 A.G, n(%) 0.05 NS

GG (*3/*3) 24 (63) 14 (37)

AG (*1/*3) 6 (67) 3 (33)

AA (*1/*1) 0 (0) 4 (100)

Cumulated sorafenib AUC (mg/L.h) 2,250 3,499 0.034 1.07 (1.01–1.12) 0.019

[1,845–2,858] [2,070–4,019]

Hand Foot Skin Reaction $ grade 2

Gender 0.024 5.26 (1.33–20.0) 0.018

Female, n (%) 5 (33.3) 10 (66.7)

Male, n (%) 25 (52.0) 12 (48.0)

ECOG PS 1 [1–2] 1 [0–1] 0.043 NS

Cumulated sorafenib AUC (mg/L.h) 2,250 3,308 0.042 NS

[1,789–2,858] [2,070–4,365]

Diarrhea $ grade 2

UGT1A9 2275 T.A 0.043 NT*

wt/wt, n (%) 43 (93) 3 (7)

wt/m, n (%) 2 (50) 2 (50)

m/m, n (%) 0 (0) 0 (0)

UGT1A9 22152 C.T 0.045 14.33 (1.46–140.50) 0.015

wt/wt, n (%) 42 (93) 3 (7)

wt/m, n (%) 2 (50) 2 (50)

m/m, n (%) 0 (0) 0 (0)

Hypertension $ grade 2

Albumin (g/L) 37 [34–40] 41 [37–42] 0.06 NS

Daily dose of sorafenib (mg/m2) 392 [232–434] 220 [177–394] 0.053 NS

AUC, area under the curve; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group Performance Status; m, mutant allele; NS, not significant; NT, nottested; OR, Odds ratio; Wt, wild-type allele.Quantitative results are expressed as median [interquartile range]*Heterozygotous patients (wt/m) for UGT1A9–2152 C.T and UGT1A9–275 T.A were the same; therefore the polymorphism for UGT1A9–275 T.A was not tested in themultivariate analysisdoi:10.1371/journal.pone.0042875.t005

PK/PD Relationship for Sorafenib-Induced Toxicity

PLOS ONE | www.plosone.org 7 August 2012 | Volume 7 | Issue 8 | e42875

Boudou-Rouquette et al., Plos one 2012

Relation PK/PD : syndrome mains pieds

11Peer et al., Clin Cancer Research 2012

Relation PK/PD : hypertension et SMP

12Fukudo et al., Clinical Pharmacokinetics, 2013

13

Relation PK/PD : efficacité CHC

Arrondeau et al., Invest New Drugs, 2012

***

* p=0.008 (vs day 30) ** p =0.007 (vs day 30)

14

Relation PK/PD : efficacité CHC

Fukudo et al., Clinical Pharmacokinetics, 2013

15Pecuchet et al., British Journal of Cancer 2012

0.40–2.28) and 0.51 (95% CI: 0.19–1.24), respectively). Thus, thediscrepancies between the three pharmacokinetic parameters(AUC at 1 month, mean and max AUC) were investigated. Indeed,6 (21%) and 8 (28%) patients were misclassified by the AUC at 1month compared with the mean AUC and the AUCmax,respectively. Moreover, despite a low mean AUC, three respondingpatients had a high AUCmax, which could explain the clinicaleffect. Conversely, four patients with a mean AUC above theaverage but low AUCmax did not respond to the treatment.

DISCUSSION

In this multi-institutional experience with sorafenib dose-escala-tion in patients with metastatic melanoma, the main resultsconsisted in the positive correlation between AUCmax, objectiveresponse and PFS. Although modest in melanoma, sorafenibefficacy was directly correlated with exposure, as seen withsunitinib in RCC and GIST (Houk et al, 2010) or pazopanib indifferentiated thyroid cancers (Bible et al, 2010). Consistently withresults from the phase I trials (Awada et al, 2005; Clark et al, 2005;Moore et al, 2005; Furuse et al, 2008; Minami et al, 2008; Miller

et al, 2009) AUC increased infra-proportionally to the dose.However, the dose-escalation schedule increased AUC in 68%(13/19) patients. In this series, dose adjustments could effectivelycorrect drug under-exposure.

To go further, the changes in sorafenib clearance andbioavalability with doses 4400 mg bid were described in a cohortof 71 patients treated with sorafenib in our institution, includingthe present series of melanoma patients (Hornecker et al, 2011).A one-compartment model with saturated absorption, first-orderintestinal loss and elimination best described the pharmacoki-netics of sorafenib. Absolute bioavailability significantly droppedwith increasing daily doses of sorafenib. Area under the curveincreased less than proportionally with increasing doses. There-fore, a split schedule three times a day might overcome absorptionsaturation, thereby leading to a higher exposure (Hornecker et al,2011). Notably, tumour type did not seem to influence sorafenibpharmacokinetics. Only albumin was found to influence sorafenibclearance at standard doses (Tod et al, 2011). As well, in anindependent cohort (Jain et al, 2011), no clinically important PKcovariates were identified.

In this series, the highest AUC (AUCmax) was correlated withantitumor efficacy while the other PK parameters were biased bythe dose-escalation schedule: the AUC at 1 month was too earlyand the mean AUC did not reflect periods of high exposure, shownto be correlated to antitumor efficacy in our study. The Youdenindex of the ROC curve of the disease control relative to theAUCmax was 100 mg l! 1 h! 1, suggesting that highest exposuresare responsible for efficacy. These properties of antiangiogenictreatments have been previously described and represented by a bell-shaped dose–response curve (Reynolds, 2009). Strikingly, only 15%of samples assessed at 400 mg bid had an AUC over 90 mg l! 1 h! 1

vs 36% of samples at 600 mg bid and more (P¼ 0.0003). With atarget AUC of 90–100 mg l! 1 h! 1, theses results pinpoint thatmost patients are underexposed to sorafenib at 400 mg bid, andthat individualised dose adjustments would be required. In linewith these results, a recent study (Motzer et al, 2011) has shownthe superiority of sunitinib 50 mg daily 4 weeks out of 6 over acontinuous daily dosing of 37.5 mg, pinpointing the need to reacha threshold exposure.

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Figure 2 Effect of dose escalation on intra patient sorafenib AUC(mg l! 1 h! 1). Median AUCs from 19 patients are represented. In red:increased exposure; in orange: stable exposure; in green: decreasedexposure.

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Figure 3 Investigator-assessed tumour regression (i.e., maximum changefrom baseline in target lesions diameter). (n¼ 27) Patients with RECISTprogressive disease are indicated by an asterix. Clear grey: AUCmaxo100 mg l! 1 h! 1; dark grey: AUCmaxX100 mg l! 1 h! 1.

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Figure 4 PFS probability according to maximal exposure to sorafenib(AUCmax). Dot line: patients with AUCmax o100 mg l! 1 h! 1/; solid line:patients with AUCmaxX100 mg l! 1 h! 1.

Sorafenib in advanced melanomaN Pecuchet et al

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& 2012 Cancer Research UK British Journal of Cancer (2012) 107(3), 455 – 461

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Relation PK/PD : efficacité mélanome


DISCUSSION






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TDM et escalade de dose

16Pecuchet et al., British Journal of Cancer 2012


DISCUSSION






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Bénéfice du TDM dans le cancer de la thyroïde

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Articles

www.thelancet.com Vol 384 July 26, 2014 323

reaction, diarrhoea, alopecia, rash or desquamation, fatigue, weight loss, and hypertension (table 2). An increase in serum thyroid-stimulating hormone concentration above 0·5 mIU/L was recorded as an adverse event in 33·3% (69/207) of patients in the sorafenib group, and hypocalcaemia in 18·8% (39/207) (table 2).

Dose interruptions, reductions, or withdrawals because of adverse events occurred in 66·2% (137/207), 64·3% (133/207), and 18·8% (39/207) of patients, respectively, receiving sorafenib, and in 25·8% (54/209), 9·1% (19/209), and 3·8% (8/209) of patients, respectively, receiving placebo. Hand–foot skin reaction was the most common reason for sorafenib dose interruptions (55/207 [26·6%]), reductions (70/207 [33·8%]), and withdrawals (11/207 [5·3%]).

Serious adverse events occurred in 37·2% (77/207) patients receiving sorafenib and in 26·3% (55/209) receiving placebo. Serious adverse events that occurred in 2% or more of patients receiving sorafenib were secondary malignancy (4·3% [9/207]), dyspnoea (3·4% [7/207]), and pleural eff usion (2·9% [6/207]); the corresponding rates with placebo were 1·9% (4/209), 2·9% (6/209), and 1·9% (4/209), respectively. In the sorafenib group, secondary malignancies occurred in nine patients, including seven with squamous cell carcinomas of the skin (one patient also had melanoma) and one each with acute myeloid leukaemia and bladder cancer. In the placebo group, there were single cases of bladder cancer, colon carcinoma, pulmonary carcinoid tumours, and gastric cancer. 12 treatment-emergent deaths occurred in the sorafenib group and six in the placebo group. In the sorafenib group, seven deaths were attributable to underlying disease, two to unknown causes, and one each to lung infection, chronic obstructive lung disease, and myocardial infarction. In the placebo group, four deaths were attributable to underlying disease and one each to pulmonary embolism and subdural haematoma. One death in each group was attributed to the study drug—myocardial infarction (sorafenib) and subdural haematoma (placebo).

Tumour mutation data were available for 256 (61·4%) patients overall: 126 in the sorafenib group and 130 in the placebo group. The genetic subpopulation was similar to the overall population, except for a lower percentage of patients from Asia (11·3% [29/256] vs 23·7% [99/417]) (appendix p 14). BRAF mutations were present in 27·0% (34/126) of tumour samples in the sorafenib group and 33·1% (43/130) of those in the placebo group, and RAS mutations in 19·0% (24/126) in the sorafenib group

Figure 2: Progression-free survival(A) Progression-free survival by central review (intention-to-treat population).

(B) Forest plot of progression-free survival in subgroups (central review). PFS=progression-free survival. HR=hazard ratio. FDG=2-(18F)-fl uoro-2-deoxy-D-

glucose. RAI=radioactive iodine. *Three patients assigned multiple histologies are excluded. †Five is the median number of lesions. ‡71 mm is the median

target lesion size.

Number at riskSorafenib

Placebo

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n Median PFS, days (months)

HR 0·59, 95% CI 0·45–0·76p<0·0001

RegionEuropeNorth AmericaAsiaAge group<60 years≥60 yearsHistology (central review)*PapillaryHürthle cellFollicular, non-Hürthle cellPoorly differentiatedLung metastases onlyNoYesBone metastasesNoYesFDG uptakeNegativePositiveNumber of target or non-target lesions<5†≥5Target lesion size<71 mm‡≥71 mmSexMaleFemaleCumulative RAI ≥600 mCiNo YesOverall

2497296

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n HR (95% CI)B

Favours sorafenib Favours placebo

1·00·5 1·50 2·0

Brose et al., Lancet 2015; Boudou-Rouquette et al., Lancet 2015

Median PFS : 26 mois (18-32) (n=8)

TDM

Gain de PFS de 15 mois par rapport à l’essai DECISION

Take home messages

18

Suivi Thérapeutique Pharmacologique

Progression

ObservanceC° Faible : optimisation de la dose

C° Correcte : recherche de résistance pharmacologique et changement de

traitement

Toxicité Interactions médicamenteuses

Populations à risque: Insuffisance hépatique, sarcopéniques,

patients âgésInhibiteurs et inducteurs CYP3A4

Médecines complémentaires

Pr F. Goldwasser:« La médecine de précision ne se réduit pas à l'analyse de la tumeur (la "cible") mais également à l'analyse du comportement de la "flèche", le médicament… »

19

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